Horii Takuro, Yamamoto Masamichi, Morita Sumiyo, Kimura Mika, Nagao Yasumitsu, Hatada Izuho
Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan.
Advanced Scientific Research Leaders Development Unit, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Sci Rep. 2015 Mar 10;5:8907. doi: 10.1038/srep08907.
Mammalian tetraploid embryos die in early development because of defects in the epiblast. Experiments with diploid/tetraploid chimeric mice, obtained via the aggregation of embryonic stem cells, clarified that while tetraploid cells are excluded from epiblast derivatives, diploid embryos with tetraploid extraembryonic tissues can develop to term. Today, this method, known as tetraploid complementation, is usually used for rescuing extraembryonic defects or for obtaining completely embryonic stem (ES) cell-derived pups. However, it is still unknown why defects occur in the epiblast during mammalian development. Here, we demonstrated that downregulation of p53, a tumour suppressor protein, rescued tetraploid development in the mammalian epiblast. Tetraploidy in differentiating epiblast cells triggered p53-dependent cell-cycle arrest and apoptosis, suggesting the activation of a tetraploidy checkpoint during early development. Finally, we found that p53 downregulation rescued tetraploid embryos later in gestation.
哺乳动物四倍体胚胎在早期发育过程中会因上胚层缺陷而死亡。通过胚胎干细胞聚集获得的二倍体/四倍体嵌合小鼠实验表明，虽然四倍体细胞被排除在上胚层衍生物之外，但具有四倍体胚外组织的二倍体胚胎可以发育至足月。如今，这种被称为四倍体互补的方法通常用于挽救胚外缺陷或获得完全由胚胎干细胞（ES细胞）衍生的幼崽。然而，哺乳动物发育过程中上胚层为何会出现缺陷仍然未知。在此，我们证明了肿瘤抑制蛋白p53的下调挽救了哺乳动物上胚层中的四倍体发育。分化中的上胚层细胞中的四倍体引发了p53依赖性细胞周期停滞和凋亡，这表明在早期发育过程中四倍体检查点被激活。最后，我们发现p53下调在妊娠后期挽救了四倍体胚胎。
